Cardiovascular disease (CVD) is arguably the greatest non-infectious health care problem ever to afflict mankind and lung disease is not far behind. Stem/progenitor cells hold great promise to replace cardiomyocytes after myocardial infarction (Ml) or alveoli after lung injury, but there is little agreement on how best to differentiate these cells and ensure in vivo functionality. Our approach to cardiac and lung regeneration/repair is innovative and based on solid preliminary findings. Indeed, collectively we have been working in this field and preparing for participation in this Consortium for more than two decades. We are committed to exploring the mechanistic underpinnings of the native myocardial repair process, discovering natural barriers that prevent effective repair, and devising synthetic small molecule and miR-based pharmaco-therapies and strategies to overcome these barriers. The overall goal of our group will be to combine the power of miRs, small molecules and native stem/progenitor cells to dissect fundamental mechanisms controlling cell fate, and to exploit these new discoveries to ultimately develop therapeutics. We propose three specific aims that will provide new starting points for therapeutic RNA and drug development, while expanding the mechanistic science of cardiac and lung regeneration and repair. The aims are: Aim 1. Define cell fate mechanisms in the native microenvironment; Aim 2. Develop a mechanistic signaling map of how pathophysiological stress/injury promotes structural and functional repair; Aim 3. Collaborate Consortium-wide to develop education programs that can steer iPS cells towards desired fates and enhance their function in vivo. To accomplish these aims, we have functionally merged two synergistic and interactive progenitor cell biology groups at Harvard and UT Southwestern, and we have already generated promising preliminary data through team science. As a member of NHLBI Progenitor Cell Biology Consortium, our proposed Hub will make substantial and important contributions to advancing this new frontier of cardiovascular and pulmonary regenerative medicine.